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Cytokine-Associated Emotional and Cognitive Disturbances in Humans
Abraham Reichenberg, PhD;
Raz Yirmiya, PhD;
Andreas Schuld, MD;
Thomas Kraus, MD;
Monika Haack, MA;
Abraham Morag, MD;
Thomas Pollmächer, MD
Arch Gen Psychiatry. 2001;58:445-452.
Background Infectious, autoimmune, and neurodegenerative diseases are associated
with profound psychological disturbances. Studies in animals clearly demonstrate
that cytokines mediate illness-associated behavioral changes. However, the
mechanisms underlying the respective psychological alterations in humans have
not been established yet. Therefore, we investigated the effects of low-dose
endotoxemia, a well-established and safe model of host-defense activation,
on emotional, cognitive, immunological, and endocrine parameters.
Methods In a double-blind, crossover study, 20 healthy male volunteers completed
psychological questionnaires and neuropsychological tests 1, 3, and 9 hours
after intravenous injection of Salmonella abortus equi
endotoxin (0.8 ng/kg) or saline in 2 experimental sessions. Blood samples
were collected hourly, and rectal temperature and heart rate were monitored
continuously.
Results Endotoxin had no effects on physical sickness symptoms, blood pressure,
or heart rate. Endotoxin caused a mild increase in rectal temperature (0.5°C),
and increased the circulating levels of tumor necrosis factor  (TNF-),
soluble TNF receptors, interleukin (IL)-6, IL-1 receptor antagonist, and cortisol.
After endotoxin administration, the subjects showed a transient significant
increase in the levels of anxiety (effect size [ES] = 0.55) and depressed
mood (ES = 0.66). Verbal and nonverbal memory functions were significantly
decreased (ES = 0.55 to 0.64). Significant positive correlations were found
between cytokine secretion and endotoxin-induced anxiety (r = 0.49 to r = 0.60), depressed mood (r = 0.40 to r = 0.75), and decreases
in memory performance (r = 0.46 to r = 0.68).
Conclusions In humans, a mild stimulation of the primary host defense has negative
effects on emotional and memory functions, which are probably caused by cytokine
release. Hence, cytokines represent a novel target for neuropsychopharmacological
research.
From the Department of Psychology, the Hebrew University, Jerusalem,
Israel (Drs Reichenberg and Yirmiya); Max Planck Institute of Psychiatry,
Munich, Germany (Drs Schuld, Kraus, and Pollmächer and Ms Haack); and
the Clinical Virology Unit, Hadassah-Hebrew University Medical Center, Jerusalem
(Dr Morag). Dr Morag is deceased.
Corresponding author: Raz Yirmiya, PhD, Department of Psychology,
the Hebrew University of Jerusalem, Jerusalem, Israel (e-mail: msrazy{at}mscc.huji.ac.il).
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